THU0546 Serum CXCL13 as A Biomarker of Disease Activity and Severity in IN Rheumatoid Arthritis. Comparison with Acute Phase Reactants and the Autoantibody Profile

Abstract

Background The B cell chemoattractant CXCL13 has recently emerged as a new candidate biomarker of disease activity capable of identifying patients with persistent synovitis and worst radiographic outcomes in early rheumatoid arthritis (RA). However, whether CXCL13 reflects underlying disease processes or simply represents another non-specific marker of inflammation is currently unknown. Objectives To analyse the clinico-pathologic significance of serum CXCL13 in comparison to routine laboratory markers of disease activity and severity in patients with RA. Methods Baseline serum levels of CXCL13 were measured by colorimetric ELISA in 205 consecutive early untreated RA patients with disease duration <12 months (median 3 months, IQR 2-5.5). Disease activity was assessed by a comprehensive set of subjective, semi-objective and objective clinical features. Changes in CXCL13 levels were evaluated in 87 patients after 2 months of treatment with methotrexate and low-dose prednisone. An additional study population of 60 RA patients (n=22 with disease duration <12 months) in whom paired serum and synovial samples were collected on the same day was used to assess the pathologic correlates of circulating CXCL13. Results In cross-sectional analyses at baseline, CXCL13 was moderately correlated with the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (rho 0.35 and 0.36 respectively, p<0.001). Similarly to acute phase reactants, CXCL13 correlated with overall disease activity as measured by the DAS28, in particular with physician-derived measures, as well as with ultrasonographic scores for Gray Scale and Power Doppler signals. In contrast to ESR and CRP, no correlation was found with patient-derived measures and functional status. Although increased CXCL13 levels were found in patients with anti-citrullinated protein antibodies (ACPA), high CXCL13 and ACPA were not synonymous. CXCL13 in the 3rd tertile (>100 pg/ml) was found in 27.9% of ACPA(−) patients, and, in turn, 53.4% of ACPA(+) patients had CXCL13 <100 pg/ml. Similar results were observed for rheumatoid factor. After 2 months of treatment, CXCL13 levels were not significantly changed from baseline, as opposite to the significant reduction of acute phase reactants (standardised response mean 0.04, 0.52 and 0.66 for CXCL13, ESR and CRP respectively). In paired serum and tissue samples, circulating CXCL13 was significantly correlated with synovial CXCL13 protein (n=60 patients, rho 0.30, p=0.04) and mRNA (n=19 patients, rho 0.56, p=0.02) expression. Similarly to ESR and CRP, serum CXCL13 was related to synovial inflammatory features such as the degree of sublining macrophage infiltration (rho 0.34, p=0.01). Serum CXCL13, but not acute phase reactants, showed further correlation with specific histopathologic and molecular synovial parameters such as the presence and density of large B cell aggregates (rho 0.28, p=0.03), expression levels of the B cell enzyme activation induced cytidine deaminase (AID) (rho 0.4, p=0.046), and the receptor activator o...

A systematic review of CXCL13 as a biomarker of disease and treatment response in rheumatoid arthritis

“…ERA, EstRA csDMARD Synovial by mRNA qPCR Not published ACPA & radiographic erosive disease associated greater expression CXCL13 (data not presented) Greisen et al (2014) [ 23 ] N = 114. ERA csDMARD, TNFi Serum by ELISA ERA > HC RA: 149 (75–245) HC: 50 (29–93) Correlation: B/L SJC28 ( r = 0.34) PGA ( r = 0.38) not TJC28 Bugatti et al* (2014) [ 24 ] N = 205 csDMARD Serum by ELISA Not published Correlation: ESR ( r = 0.35), CRP ( r = 0.36) DAS28 & US grey scale/power doppler (data not presented) Moura et al (2014) [ 25 ] Unpublished Serum by ELISA ERA/EstRA > HC Not published No correlation: DAS28-ESR, ESR, SJC28, TJC28 (data not presented) Jones et al (2014) [ 26 ]. EstRA N = 193 ERA N = 339 Serum by ELISA EstRA RF+: 331 (250–431), EstRA RF-: 93 (71–124), ERA RF+: 324 (224–478), ERA RF-: 50 (35–78) Correlation DAS28-CRP (r = 0.52) in EstRA.…”

“…ERA csDMARD, Anti-TNF Cohort Serum by ELISA Correlate with treatment response. B/L high level predict ADA treatment remission Bugatti et al* (2014) [ 24 ] N = 205 csDMARD Cohort Serum by ELISA No change with treatment de Jong et al (2014) [ 35 ] N = 18 Anti-CD20 Cohort Serum by Luminex Reduction with rituximab irrespective of responder status El-Sherbiny et al* (2013) [ 36 ] N = 23 Anti-CD20 Cohort Synovial by mRNA qPCR Reduction with rituximab in rituximab responders Taylor et al (2017) * [ 37 ] N = 65 EstRA JAKi RCT Serum, method not published Reduction with filgotinib. No change with placebo Gabay et al (2016) [ 38 ] N = 356 EstRA Anti-IL6R RCT Serum by ELISA Reduction with sarilumab ( p < 0.01) from 2 weeks Boyle et al (2015) [ 39 ] N = 29 EstRA JAKi RCT Serum by ELISA Reduction with tofacitinib.…”

“…One study reported a correlation with patient-derived measures (patient global assessment) [ 23 ]. Four studies examined CXCL13 as a marker of ultrasound synovitis, reporting a correlation with ultrasonographic scores for Grey Scale ( r = 0.27) [ 24 , 31 ] and Power Doppler signals ( r = 0.26–0.69) [ 24 , 21 , 29 , 31 ]. Four studies evaluated the association between CXCL13 level and seropositivity (RF and CCP).…”

“…A number of synovial inflammatory markers correlate with CXCL13 synthesis [ 31 , 44 ] and levels reflect the extent of synovial inflammation in clinical and imaging evaluation [ 31 ]. The inflamed rheumatoid synovium significantly contributes to serum CXCL13 levels, with a strong relationship between synovial expression and serum level [ 24 , 26 ]. This is in contrast to acute phase proteins, which are primarily produced by hepatocytes released during inflammation, or other cytokines expressed in the synovium which are low or undetectable in the serum.…”

“…Three studies found no change in levels with treatment. With methotrexate initiation, in contrast to the early reduction in acute phase markers, CXCL13 levels did not significantly change, reflecting a more persistent pattern of synovial inflammation [ 24 ].…”